Since the 1930's, when Crohn's Disease was separated and disregarded as an infectious bacterial disease, research efforts have largely been directed at superficial disease issues. That is not to say that a great deal of valuable information has not been derived from these studies, but only that the patients themselves have generally not benefited from those efforts.

In the 1930's and 1940's, the cause of Crohn's disease was considered a psychosomatic disorder

Once Crohn's Disease became an idiopathic (meaning "we do not know") disease, there was an effort to identify the cause or, at least, associate the disease with a cause. In the 1950's, it was assumed that Crohn's Disease was "all in your mind", a psychosomatic disorder and the recommended treatment was a psychiatrist. This erroneous diagnosis lasted for years: the medical community has historically been slow to change. When the age of immunology arose in the 1960's, everything was considered to have an immunologic cause, including Crohn's Disease. Because the symptoms of Crohn's Disease tended to subside with the administration of anti-inflammatory and immunosuppressive agents and the "in thing" at the time was auto-immunity, the logical conclusion was that Crohn's Disease was also an autoimmune disease. But the only evidence for this was the symptomatic response to these immunosuppressive drugs - there was no other evidence and Crohn's Disease does not even have the characteristics or fit the criteria to be classified as an autoimmune disease. Nonetheless, many physicians, and thus their patients, continue to believe that Crohn's Disease is an autoimmune disease like Rheumatoid arthritis. Unfortunately, although the autoimmune theory has been unequivocally dismissed for over 20 years, many physicians and gastroenterologists cling to this theory - the medical community has historically been slow to change.

Because of the autoimmune theory, for the next 50 or so years, research efforts have been focused on mucosal immunology (the immune response of the gastrointestinal tract) in that futile effort to find that link causing the overly aggressive and destructive immune response and/or what part of the body the immune system was attacking (clinging to the autoimmune theory). From these efforts, which continue to this date, we have learned a great deal about the immune system, particularly that associated with the gut, but we have not moved any closer to finding the cause of Crohn's Disease and the patients themselves have benefited little in the long run.

We are now in the Genomics Era and are beginning to understand what our genes actually code for and how they relate to various diseases. We are also beginning to understand the vast array of bacteria that inhabit our body and how these bacteria contribute to our health and well-being. Welcome to the Age of Genetics.

The Age of Genetics

As in other diseases, genes that make an individual susceptible to Crohn's Disease have been discovered. The most common susceptibility genes are known as NOD2/CARD15, ATG16L1, and IRGM. These genes code for immune functions related to bacterial recognition (NOD2/CARD15) or the killing of bacteria (ATG16L1 and IRGM) by a method known as autophagy. This is a basic and primordial defense mechanism against bacteria and has a profound effect on our natural (innate) and learned (adaptive) immune responses.

It means that Crohn's Disease is an immune deficiency disease (broadly speaking) and not psych-somatic or autoimmune. It means that, if Crohn's Disease is an immune deficiency disease, is treating with drugs that suppress the immune system the logical approach? It means that, if Crohn's Disease relates to an immune deficiency in the recognition and killing of bacteria, has the medical community wasted over 90 years in largely ignoring bacteria as a cause of Crohn's Disease? The medical community has historically been slow to change.

Genetic studies have identified immune deficiencies as a susceptibility factor in Crohn's disease

The general descriptive cause of Crohn's Disease is often said to be "A unique combination of genetic predisposition and environmental triggers that result in immunologic dysregulation releasing a cascade of immunologic inflammatory mediators that result in hyper-responsiveness within the gastrointestinal tract". This description has little meaning as it only tells us what the effect of the disease is, not the cause.

But we now know that the "genetic predisposition" in Crohn's Disease is related to the ability to recognize and kill certain bacteria, so this description needed some tweaking and has now been changed to something to the effect of "Crohn's disease is caused by an overly aggressive immune response to normal commensal enteric bacteria; i.e., the complex microbiome of the distal ileum and colon provide a constant source of antigens that stimulate chronic inflammation in genetically susceptible hosts."

The key word in that description is "normal commensal bacteria". This description is rooted in 2 basic concepts. The first being genetics as discussed above and the second is related to the gastrointestinal microbiome, which is now the "in thing".

Everyone has heard of the Human Genome Project to sequence the human genome, but an equally important project is the Human Microbiome Project (being conducted in the United States) and the MetaHIT Project (Metagenomics of the Human Intestinal Tract) in Europe. The purpose of these projects are to identify all of the microbial organisms that inhabit the human body, collectively known as the microbiome. We are hosts, and provide the environment and home, to support the life of an estimated 40,000 different bacteria. In return, these bacteria provide us with essential elements we need for normal human physiology, metabolism, energy harvest, homeostasis of the immune system, and protect us against pathogens (the bad bacteria). They need us as much as we need them.

It did not take long before the fecal material of Crohn's Disease patients were examined and compared to that of normal healthy individuals. What they found was that the bacterial communities in Crohn's Disease were altered with the "good" bacteria being over-run with "not-so-good" bacteria, a condition termed "dysbiosis". Thus, it was concluded that this dysbiosis was the cause of the inflammation and the cause of Crohn's Disease was attributed to "normal commensal enteric bacteria". Again, the medical community jumped the gun.

The disruption in normal bacterial homeostasis of the gut contributes to many of the symptoms in Crohn's disease

We now know that dysbiosis is a common occurrence during any disease or gastrointestinal disturbance and a variety of factors can cause dramatic changes in microbial communities including diet, smoking, and changes in the hosts' cellular tissue composition (such as that occurring during disease). Every time you have diarrhea, regardless of the reason, your fecal bacterial communities will change and be different, i.e., become dysbiotic. If this is not enough compelling evidence that dysbiosis is not the cause of Crohn's Disease, recent evidence conclusively shows that dysbiosis is the result of inflammation, not the other way around.

Also, since different bacteria inhabit different parts of the intestinal tract, how likely is it that completely different bacteria in the colon and the proximal small intestines (and elsewhere) cause the same type of disease? It was not only a premature leap of faith to suggest that disease is caused by commensal bacteria before data was available, but it was as irresponsible as suggesting Crohn's disease was a psychosomatic or autoimmune disease.

There is no question that this altered dysbiotic state contributes to many of the symptoms of Crohn's Disease, but again it is not the cause but rather the effect. By the same token, inflammation causes many of the symptoms of Crohn's Disease, and while inflammation might be the cause of your symptoms, it is not the cause of the disease.

So, in summary, what is really known about the cause of Crohn's Disease?

That there is a genetically-based immune deficiency related to the recognition and killing of bacterial agents.

That bacteria are directly involved in both the cause and effects of the disease.

That the immune-deficiency alone is not sufficient to result in disease (i.e., the deficiency just puts you at higher risk, it does not mean you will get the disease - there are many healthy individuals with these same deficiencies).

That leaves us with bacteria as the cause of the inflammation. But there is clearly 2 situations occurring simultaneously, one specific and one non-specific.

It has long been known that there is increased bacterial translocation across the mucosal barrier in Crohn's disease. That is to say that there are increased numbers of bacteria getting through the barriers of the intestinal tract from the intestinal lumen into the underlying tissues. This has sometimes been called the "leaky gut" syndrome. These bacteria, crossing into the body, undoubtedly contribute greatly to the inflammatory response and many of the clinical symptoms of the disease.

There is little doubt that these commensal bacteria, penetrating the mucosal barrier, are a major contributing factor in the disease process. These bacteria create a cesspool within the intestinal submucosa. It may be possible that without these commensal bacteria penetrating the gut wall, overt clinical disease may not fully develop (at least with the severity of Crohn's disease). But these commensal bacteria are not the cause of the actual disease but a consequence thereof - It is like an infected wound.

Think of Crohn's disease as an infected wound, a cut on your skin that is infected. You can apply topical steroids or other anti-inflammatory and immunosuppressive agents and you will feel better - the pain and itching will subside and so will be redness (inflammation). Although you may be feeling better, you know that your cut is not really getting better and probably getting worse. Eventually the topical steroids will not be enough to make you feel better and more powerful drugs will be needed. Infliximab (Remicade) will work to make you feel better, at least for awhile, but the wound will not heal. This is what is happening in Crohn's disease.

The question remains as to what creates that initial wound that causes the increased bacterial translocation that allows this cesspool to develop. There is more than these commensal bacteria and the resulting dysbiosis; these are all effects like an infected wound and not the cause. There is something that starts the whole cascade of events, something that is commonly referred to as the "trigger".

The Specific Response: "The Trigger"

The "trigger" is what starts the entire cascade of events that leads to Crohn's disease and is the real cause of the disease, not all the superficial epiphenomena that are the result of the disease. Only by the identification of this trigger can we begin to understand Crohn's disease and find a cure. We may learn that once this trigger is identified, Crohn's disease may not be as complex a disease as we now assume. There are sufficient clues available to point us in the right direction to find this trigger, should the medical community choose to pursue that path.

The "trigger" disrupts the integrity of the mucosal barrier and the resulting inflammation augments the infiltration of commensal bacteria which further drive the inflammatory response.

The occurrence of skip lesions (normal tissue between diseased segments) is evidence that the disease starts at one or more distinct localized centers and does not occur diffusely, i.e., spread out as would be expected for an autoimmune disease or an allergy (like gluten). There is also evidence that, other than the gastrointestinal tract, there is no specificity as where these localized centers may occur; they may occur in the small or large bowel or both, and anywhere therein. Disease may also occur at multiple remote and unrelated sites such as in the esophagus or mouth.

These features suggest that this "trigger" has an environmental source (as opposed to the host/patient) and that exposure to that trigger is not common. If the "trigger" were common (e.g., gluten in bread) or from the host (e.g., autoimmunity), you would have more diffuse inflammation and not localized centers. This simple feature alone allows us to conclude that the trigger is an uncommon environmental factor.

Knowing that it is likely an uncommon trigger from the environment, does the trigger come and go (cause its damage and then disappear) or does it remain to continuously drive the inflammation? Evidence suggests the latter: the "trigger" remains and it is not a "hit and run" type situation.

Ignoring the fact that "hit and run" scenarios usually result in more widespread effects (like autoimmunity), the strongest support for the proposition that there exists a continuous trigger comes from surgery. When diseased intestinal tissues are removed surgically, the disease invariably returns at the point of anastomosis (reconnection site). The most logical conclusion is that the trigger is not removed by surgery. This makes sense because patients are generally treated with anti-inflammatory and immuno-suppressive drugs, thereby making it very difficult for the surgeon to determine where the disease starts and ends. In all likelihood, all of the diseased tissue is not removed surgically - the "normal" tissue appears normal to the surgeon only because the inflammation is artificially reduced by chemotherapeutic agents. Thus, the site of anastomosis is still diseased and disease recurs at the anastomosis site. It would be too much of a coincidence to suggest that re-exposure to the "trigger" always occurs at the site of reconnection.

We can also conclude from these observations that the location of the "trigger" is not limited to the center of the disease with an expanding inflammatory response, but rather that the inflammation follows a moving "trigger". In other words, the "trigger" exists on the outer margins of the disease.

Let's now examine the occurrence of remote sites of Crohn's disease, such as those occurring in the mouth or esophagus. These lesions almost always occur secondary to primary disease in the ileum and/or colon. These secondary sites are also clues as to the nature of the "trigger".

There are only 2 possible mechanisms by which these secondary sites can occur: by exogenous exposure (re-exposure to the "trigger" from the environment) or by endogenous exposure (re-exposure to the "trigger" from the primary lesion). Data clearly establishes that the primary target (where the disease starts) of the "trigger" is the ileum/colon and not these remote sites and there are no cases of Crohn's disease being limited to these remote sites without a primary lesion in the ileum or colon. It is therefore reasonable to conclude that these remote sites represent endogenous exposure akin to the spread of cancer known as metastatic lesions.

The "trigger" disrupts the integrity of the mucosal barrier and the resulting inflammation augments the infiltration of commensal bacteria which further drive the inflammatory response.

For endogenous exposure to occur, the "trigger" must be transported by the blood stream to these secondary sites. Since the primary lesion(s) does not resolve with the occurrence of secondary disease in remote sites, it must be concluded that the "trigger" remains at the original site and that additional "triggers" are being transported to the new site(s). If this is true, it can only mean that the "trigger" is increasing in number within the primary disease site.

Reviewing the information compiled above, we can conclude that Crohn's disease is caused by a "trigger" that:

Takes advantage of a genetic defect in the recognition and killing of intracellular organisms.

Comes from the environment, but is not common therein and exposure is a relatively rare event.

Has the ability to cause chronic granulomatous inflammatory responses.

Has a predilection for the gastrointestinal tract, particularly the ileum and colon.

Initially causes one or more distinct focal lesions that may later coalesce as the disease progresses.

Remains throughout the diseased tissue, including the outer margins.

May cause disease in remote sites most likely by endogenous exposure to the "trigger".

Causes super-infection of the lesion by other bacteria creating a cesspool within the affected tissue.

The only thing that can account for these features is an infectious agent. Unfortunately, the medical community has been reluctant to even consider an infectious agent as the cause of Crohn's disease. Most of this reluctance is based on misinformation and reliance on information from classical types of microbial infections.

The "trigger" as an infectious agent

When the "trigger" is looked upon as an infectious agent, everything fits nicely into place and there are many examples that can be drawn upon to corroborate the role of an infectious agent.

As previously noted, susceptibility to Crohn's disease appears to be an immune deficiency related to the ability to recognize and kill certain types of intracellular bacteria. It is unlikely just a coincidence that the genes that code for susceptibility to Crohn's disease are the same genes that make an individual susceptible to various diseases caused by bacteria of the Phylum Actinobacteria, most notably M. tuberculosis (the causative agent of human tuberculosis), M. leprae (the causative agent of human leprosy or Hansen's disease), and M. paratuberculosis (the causative agent of Johne's disease or paratuberculosis in animals). Using these 3 well-known diseases as a template, Crohn's disease can be explained. That is not necessarily to suggest that one of these organisms is the cause of Crohn's disease, but perhaps a similar or related organism amongst the more than 32,000 unknown bacteria that we as humans are exposed to.

Think of Crohn's disease as an infected wound. A "trigger" started the would and problem but other bacteria have complicated and augmented the problem.

Above we compared Crohn's disease to an infected wound as a way explain the cesspool that develops within the diseased intestinal tissues. A similar situation occurs in human leprosy whereby the initial lesion caused by the "trigger" (M. leprae) becomes super-infected with other organisms. Because of the predominance of certain bacteria within the leprosy lesions, these have been called leprosy-associated Corynebacteria and greatly contribute to the disease process. As in Crohn's disease, the leprosy lesion becomes a cesspool. Super-infection with other organisms (commensal) is also common in pulmonary tuberculosis and it likely occurs with paratuberculosis as well.

The occurrence of skip lesions is also a common characteristic of an infectious organism including those of the Phylum Actinobacteria. These types of lesions generally occur when the host is exposure to multiple infectious agents either initially or as a result of exogenous or endogenous re-infection (discussed below). Although skip-type lesions (healthy tissue interspersed with diseased tissue) does occur in tuberculosis when more than one lesion (focus of infection) occurs, these skip lesions are most prominent in paratuberculosis of animals; an inflammatory bowel disease of animals. Because these animals are often exposed multiple times and/or develop multiple infections at the same time, the early stages of disease are characterized by segmental intestinal disease, i.e., skip-lesions. As the inflammation and disease progresses, these skip-lesions eventually coalesce.

Except in areas where certain diseases are endemic, bacterial pathogens are not commonly found in the environment. If they were, we would all be dying from the plaque, tuberculosis, whooping cough, leprosy, etc. A bacterial pathogen, distinct from common environmental organisms, represents an uncommon environmental source of the "trigger".

Many bacteria home to specific tissues and start as discrete foci that eventually merge to form a single diseased area, such as leprosy depicted above that homes to the skin.

Certain bacteria have a predilection for certain types of tissues. The causative agent of tuberculosis, Mycobacterium tuberculosis, has a predilection for the lungs because of its requirement for high oxygen tension. The causative agent of leprosy, Mycobacterium leprae, has a predilection for the skin because of temperature. The causative agent of paratuberculosis in animals, Mycobacterium paratuberculosis, has a predilection for the gastrointestinal tract, particularly the ileum and colon; the mechanism or why this organism has this predilection is unknown. Thus, bacterial pathogens, particularly those of the Phylum Actinobacteria, can be very tissue specific and fit the requirements of the "trigger" in Crohn's disease.

Most bacterial infections are characterized by large numbers of organisms in the tissues that are readily cultured and visualized under the microscope. We already know that 80% of the bacteria in the environment and those than make up the human microbiome cannot be cultured and are essentially unknown. It may therefore be premature to make judgment and conclusions based on our limited information. Despite this lack of knowledge, there are known bacterial diseases where the organism cannot be cultured, are difficult to visualize, and exist on the margins of the diseased tissues rather than in the center of the lesion. Paucibacillary leprosy (also known as tuberculoid leprosy) is generally characterized by the inability to visualize or detect the causative agent (M. leprae) and, when detected, are only found in the advancing disease margin and not generally within the center of the diseased tissue.

Secondary lesions from exogenous and endogenous re-infection at the primary and remote sites are also common features of bacterial infections. This feature has been most studied in human tuberculosis as it forms the basis of the tuberculosis vaccine failure. Once an individual is infected, the organism will enter the blood stream and then return to the lungs (or get lodged in a remote site) to re-infect a new area. This is called endogenous re-infection (from within) as opposed to exogenous re-infection which occurs as a secondary infection from the environment. The same is likely to occur in paratuberculosis in animals as it is known that the organism, M. paratuberculosis, enters the bloodstream and homes to the gastrointestinal tract.

Lastly, we must consider the ability of bacterial agents to cause a chronic granulomatous inflammatory response like that seen in Crohn's disease. It is indisputable that bacteria are capable of causing disease, including intestinal, that meet the granulomatous chronic inflammatory characteristics of Crohn's disease. In fact, certain chronic bacterial infections of the intestines are commonly mistaken as Crohn's disease and, prior to the 1930's, Crohn's disease was considered a form of intestinal tuberculosis similar to paucibacillary leprosy called hypertrophic intestinal tuberculosis. Organisms of the Phylum Actinobacteria clearly have the ability to cause chronic granulomatous inflammation.

In summary, viewing Crohn's disease as an infectious disease, particularly by organisms of the Phylum Actinobacteria, all the factors required for the "trigger" are present:

Bacteria of the Phylum Actinobacteria have a demonstrated ability to cause all the symptoms of Crohn's disease and act as the "trigger" of the disease.

The organism(s) take advantage of a genetic defect in the recognition and killing of intracellular organisms (e.g., tuberculosis, leprosy, paratuberculosis).

The organism(s) come from the environment, but is not common therein and exposure is a relatively rare event (e.g., tuberculosis, leprosy, paratuberculosis).

The organism(s) have a predilection for specific tissues including the gastrointestinal tract, particularly the ileum and colon (e.g., paratuberculosis).

The organism(s) initially cause one or more distinct focal lesions that may later coalesce as the disease progresses (e.g., tuberculosis, leprosy, paratuberculosis).

The organism(s) remains throughout the diseased tissue, including the outer margins (e.g., leprosy, paratuberculosis)

The organism(s) may cause disease in remote sites most likely by endogenous exposure to the "trigger" (e.g., tuberculosis, paratuberculosis).

The organism(s) cause super-infection of the lesion by other bacteria creating a cesspool within the affected tissue (e.g., tuberculosis, leprosy, paratuberculosis).

It is clearly time for a concerted effort to be undertaken to thoroughly examine the role of infectious agents as causative factors ("trigger") in Crohn's disease. Although infectious agents have been sought in the past, most of these efforts have been small and used methods that can now be considered obsolete.

We are focusing our efforts on seeking an infectious agent as the "trigger" for Crohn's disease by the following approaches:

Determining the presence of invasion and other disease-associated bacterial genes.
There are known bacterial genes that allow microbes to invade intestinal tissues and cause disease, but it is unknown how many related genes exist in unknown bacteria. By seeking to define the presence of these types of genes, we may be able to identify suspect organisms that are below normal detection methods or identify unknown organisms containing these or related genes.